Serious problems associated with cancer chemotherapy include intrinsic resistance to an anticancer agent, which invalidates the effect of the anticancer agent from the beginning of cancer therapy, and development of acquired resistance to an anticancer agent (i.e., reduction of the effect of the drug, which is caused by long-term continuous administration thereof). Overcoming such resistance to anticancer agents has been envisaged to lead to improvement in the performance of cancer chemotherapy, and thus attempts have been made to elucidate various resistance mechanisms. Particularly, expression of a drug transporter, which actively transports an anticancer agent out of cancer cells, thereby reducing the amount of intracellular accumulation of the drug, is considered to play an important role in such a resistance mechanism.
P-glycoprotein, in particular, which is a drug transporter discovered in the 1970s and is encoded by an MDR1 gene, has been considered a potent target molecule of a multidrug-resistance-overcoming agent, since this protein causes cross-resistance to a plurality of anticancer agents having different chemical structures and action mechanisms. However, it has been gradually elucidated that the anticancer agent resistance mechanism cannot be analyzed on the sole basis of P-glycoprotein, and demand has arisen for development of a resistance-overcoming agent which targets another drug transporter.
Under such circumstances, there was discovered, in 1998, breast cancer resistance protein (BCRP, also called ABCG2, MXR, or ABCP), which is a drug transporter belonging to a group which is called “ATP-binding cassette (ABC) transporter superfamily” to which P-glycoprotein also belongs (see Non-Patent Document 1). BCRP has a structure including only one ATP-binding cassette, which differs from that of P-glycoprotein or another ABC transporter, which has two ATP-binding cassettes. BCRP is involved in the mechanism of resistance to a topoisomerase I inhibitor (e.g., irinotecan hydrochloride (CPT-11) or topotecan), to a topoisomerase II inhibitor (e.g., mitoxantrone), or to a molecule-targeting therapeutic drug (e.g., gefitinib and imatinib). Meanwhile, BCRP has been elucidated to exhibit substrate specificity different from that of P-glycoprotein, since BCRP does not act on, for example, paclitaxel or vincristine, which is excreted by P-glycoprotein, and BCRP is involved in excretion of a camptothecin derivative (e.g., CPT-11 or 7-ethyl-10-hydroxycamptothecin (SN-38: active metabolite of CPT-11), which is barely excreted extracellularly by P-glycoprotein (see Non-Patent Document 2). In addition, BCRP has been suggested to be involved in the limitation of the bioavailability of an orally administered anticancer agent (see Non-Patent document 3). In view of the foregoing, demand has arisen for development of a BCRP inhibitor, which is envisaged to exhibit the effect of overcoming anticancer agent resistance that is not overcome by a conventional resistance-overcoming agent, and to improve the bioavailability of an anticancer agent.
Hitherto, in an attempt to overcome resistance to anticancer agents, a variety of P-glycoprotein inhibitors have been developed. In contrast, only a few reports have been given for BCRP inhibitors, and the reported inhibitory action is not satisfactory. Therefore, continuous efforts have been made to develop more effective BCRP inhibitors. Examples of the compounds exhibiting BCRP inhibitory action which have heretofore reported include an FTC (Fumitremorgin C) derivative (see Non-Patent Document 4), estrogen and anti-estrogen (see Non-Patent Document 5), and novobiocin (see Non-Patent Document 6). The present inventors also found that a flavonoid (see Patent Document 1) and a diphenylacrylonitrile derivative (see Patent Document 2) have potent BCRP inhibitory action.
Meanwhile, regarding acrylonitrile derivatives having a heterocyclic ring, an anticancer agent activated by CYP1B1 (see Patent Document 3), and 12-lipoxygenase inhibitor (Patent Document 4) have been reported. However, there have never been reported an acrylonitrile derivative having a heterocyclic ring which can serve as a BCRP inhibitor, an agent for overcoming resistance to anticancer agent, and an agent for potentiating anticancer agent effect.
Patent Document 1: WO 2004/069233
Patent Document 2: WO 2004/069243
Patent Document 3: WO 99/40056
Patent Document 4: JP-A-7-48336
Non-Patent Document 1: Proc. Natl. Acad. Sci. USA, 1998, 95: 15665-15670
Non-Patent Document 2: Cancer Res., 1999, 59: 5938-5946
Non-Patent Document 3: J. Clin. Oncol., 2002, 20: 2943-2950
Non-Patent Document 4: Mol. Cancer. Ther., 2002, 1: 417-425
Non-Patent Document 5: Mol. Cancer. Ther., 2003, 2: 105-112
Non-Patent Document 6: Int. J. Cancer, 2004, 108: 146-151